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1.
Bratisl Lek Listy ; 121(1): 73-78, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31950843

RESUMO

AIM: The aim of the present study was to investigate the immunohistochemical expression of selected collagen types, namely collagen types I and V and procollagen type III in the renal parenchyma and interstitium and in the myocardium of spontaneously hypertensive rats. MATERIAL AND METHODS: For the present study, we used two age groups of 6- and 12-month-old spontaneously hypertensive rats. An immunohistochemical analysis was conducted with monoclonal antibodies against collagen types I and V and procollagen type III. A semi-quantitative analysis of immunostaining intensity was conducted with the Image J software. RESULTS: In the kidney, all three molecules showed higher expression at the age of 12 months, which was particularly notable for procollagen type III and collagen type V, which stained as highly-positive. In the myocardium, the immunoreactivity of collagen types I and V was stronger in 12-month-old animals, while that of procollagen type III did not change substantially. CONCLUSION: The present study suggests a role of collagen types III and V in hypertensive kidney disease, while also establishing the role of increased expression of collagen types I and V in adverse myocardial remodeling (Tab. 1, Fig. 2, Ref. 48).


Assuntos
Hipertensão , Rim , Miocárdio , Animais , Colágeno/metabolismo , Coração , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Remodelação Vascular
2.
Clin Sci (Lond) ; 134(2): 289-302, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31961431

RESUMO

Preeclampsia (PE) is regarded as a pregnancy-associated hypertension disorder that is related to excessive inflammatory responses. Although the gut microbiota (GM) and short-chain fatty acids (SCFAs) have been related to hypertension, their effects on PE remain unknown. We determined the GM abundance and faecal SCFA levels by 16S ribosomal RNA (rRNA) sequencing and gas chromatography, respectively, using faecal samples from 27 patients with severe PE and 36 healthy, pregnant control subjects. We found that patients with PE had significantly decreased GM diversity and altered GM abundance. At the phylum level, patients with PE exhibited decreased abundance of Firmicutes albeit increased abundance of Proteobacteria; at the genus level, patients with PE had lower abundance of Blautia, Eubacterium_rectale, Eubacterium_hallii, Streptococcus, Bifidobacterium, Collinsella, Alistipes, and Subdoligranulum, albeit higher abundance of Enterobacter and Escherichia_Shigella. The faecal levels of butyric and valeric acids were significantly decreased in patients with PE and significantly correlated with the above-mentioned differential GM abundance. We predicted significantly increased abundance of the lipopolysaccharide (LPS)-synthesis pathway and significantly decreased abundance of the G protein-coupled receptor (GPCR) pathway in patients with PE, based on phylogenetic reconstruction of unobserved states (PICRUSt). Finally, we evaluated the effects of oral butyrate on LPS-induced hypertension in pregnant rats. We found that butyrate significantly reduced the blood pressure (BP) in these rats. In summary, we provide the first evidence linking GM dysbiosis and reduced faecal SCFA to PE and demonstrate that butyrate can directly regulate BP in vivo, suggesting its potential as a therapeutic agent for PE.


Assuntos
Ácidos Graxos Voláteis/análise , Microbioma Gastrointestinal/fisiologia , Hipertensão/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Adulto , Animais , Bactérias/classificação , Bactérias/genética , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Butiratos/administração & dosagem , Butiratos/análise , Butiratos/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fezes/química , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Humanos , Hipertensão/metabolismo , Hipertensão/microbiologia , Ácidos Pentanoicos/análise , Ácidos Pentanoicos/metabolismo , Dinâmica Populacional , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/microbiologia , Gravidez , RNA Ribossômico 16S/genética , Ratos Sprague-Dawley
3.
J Sci Food Agric ; 100(1): 315-324, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31525262

RESUMO

BACKGROUND: In order to utilize tilapia skin gelatin hydrolysate protein, which is normally discarded as industrial waste in the process of fish manufacture, we study the in vivo and in vitro angiotensin-I-converting enzyme (ACE) inhibitory activity of the peptide Leu-Ser-Gly-Tyr-Gly-Pro (LSGYGP). The aim was to provide a pharmacological basis of the development of minimal side effects of ACE inhibitors by comparative analysis with captopril in molecular docking. RESULTS: This peptide from protein-rich wastes showed excellent ACE inhibitory activity (IC50  = 2.577 µmol L-1 ) and exhibited a mixed noncompetitive inhibitory pattern with Lineweaver-Burk plots. Furthermore, LSGYGP and captopril groups both showed significant decreases in blood pressure after 6 h and maintained good digestive stability over 4 h. Molecular bond interactions differentiate competitive captopril upon hydrogen bond interactions and Zn(II) interaction. The C-terminal Pro generates three interactions (hydrogen bonds, hydrophilic interactions and Van der Waals interactions) in the peptide and effectively interacts with the S1 and S2 pockets of ACE. CONCLUSION: LSGYGP, with an IC50 value of 2.577 µmol L-1 , has an antihypertensive effect in spontaneously hypertensive rats. Through comparison with captopril, this study revealed that LSGYGP may be a potential food-derived ACE inhibitory peptide and could act as a functional food ingredient to prevent hypertension. © 2019 Society of Chemical Industry.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Captopril/química , Hipertensão/tratamento farmacológico , Peptídeos/química , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Captopril/administração & dosagem , Ciclídeos , Digestão , Proteínas de Peixes/química , Trato Gastrointestinal/metabolismo , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Cinética , Masculino , Simulação de Acoplamento Molecular , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/química , Hidrolisados de Proteína/metabolismo , Ratos , Ratos Endogâmicos SHR
4.
Adv Clin Exp Med ; 28(11): 1571-1575, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31756066

RESUMO

Despite great advances in medicine, the proper treatment of arterial hypertension (AH), diabetes mellitus (DM) and chronic kidney disease (CKD) remains a major challenge. Untreated, undiagnosed AH or DM may lead to the development of CKD and consequently to the occurrence of cardiovascular events. Adropin and irisin are newly discovered proteins which may play a role in the development and progression of the chronic diseases mentioned above. Endothelium dysfunction could be a bonding point. The following review paper focuses on adropin and irisin concentrations and their correlations in AH, DM and CKD. Lower adropin concentrations have been measured in patients with primary AH when compared to healthy volunteers. Irisin has reduced blood pressure on nitric oxide (NO)-dependent pathways in experimental studies; a negative correlation between irisin and blood pressure values has also been observed in preeclamptic women. Irisin also plays a role in insulin sensitivity and metabolic disorders. Lower irisin levels have been observed in patients with DM type 2 in comparison to a nondiabetic control group. It is also lower in the serum of pregnant women with gestational DM. A negative correlation between irisin and estimated glomerular filtration rate (EGFR) has also been noted. Adropin and irisin are newly described myokines measured in human plasma in healthy and disease status. Their exact function has not been specified yet and requires further studies.


Assuntos
Diabetes Mellitus/fisiopatologia , Fibronectinas/sangue , Hipertensão/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos/sangue , Insuficiência Renal Crônica/fisiopatologia , Biomarcadores/sangue , Proteínas Sanguíneas , Diabetes Mellitus/sangue , Diabetes Mellitus/metabolismo , Fibronectinas/metabolismo , Humanos , Hipertensão/sangue , Hipertensão/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/metabolismo
5.
Nat Med ; 25(11): 1733-1738, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700171

RESUMO

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Hiperfagia/genética , Obesidade/genética , Adolescente , Adulto , Criança , Metabolismo Energético/genética , Feminino , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperfagia/complicações , Hiperfagia/metabolismo , Hiperfagia/patologia , Hipertensão/complicações , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Fatores de Risco , Adulto Jovem
6.
Nat Med ; 25(11): 1657-1666, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700185

RESUMO

The prevalence of cardiometabolic disorders in both women and men has increased worldwide and is linked to a rise in obesity and obesity-associated associated clustering of other cardiometabolic risk factors such as hypertension, impaired glucose regulation and dyslipidemia. However, the predominance of common types of cardiometabolic disorders such as heart failure, atrial fibrillation and ischemic heart disease is sex specific, and our identification of these and the underlying mechanisms is only just emerging. New evidence suggests that sex hormones, sex-specific molecular mechanisms and gender influence glucose and lipid metabolisms, as well as cardiac energy metabolism, and function. Here we review sex differences in cardiometabolic risk factors, associated preclinical and clinical cardiac disorders and potential therapeutic avenues.


Assuntos
Doenças Cardiovasculares/metabolismo , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Metabolismo Energético , Feminino , Glucose/metabolismo , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/patologia , Metabolismo dos Lipídeos/genética , Masculino , Síndrome Metabólica/patologia , Obesidade/patologia , Fatores de Risco , Caracteres Sexuais
7.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(4): 381-384, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31701728

RESUMO

OBJECTIVE: To investigate the expression of 2-type small conductance-Ca2+-activating-K+ (SK2) channel protein in hypertensive rat myocardial cells. METHODS: Twelve healthy adult male SD rats were randomly divided into control group (n=5) and experimental group (n=7). The rats of experimental group were injected intraperitoneally with N'-nitro-L-arginine (L-NNA 15 mg/(kg·d))while the rats of control group were injected intraperitoneally with isometrical normal saline(15 ml/(kg·d )). The body weight, blood pressure and electrocardiogram of the rats were measured every week. After 4 weeks, the rats were sacrificed to obtain hearts, and the expression of SK2 channel protein in myocardium was detected by Western blot. RESULTS: After 4 weeks of administration, compared with the control group, the blood pressure in the experimental group was significantly elevated (P<0.05), QRS duration and R-R interval were prolonged, and the expressions of SK2 channel in the atrial and ventricular tissue of the experimental group were significantly higher than those in the control group (1.12±0.18,1.64±0.26, P < 0.05). CONCLUSION: The expressions of atrial and ventricular SK2 pathway are increased in hypertensive model rats. It may be one of the mechanism leading to arrhythmias in hypertensive model rats and can provide new ideas and strategies for the treatment and prognosis of hypertensive diseases.


Assuntos
Hipertensão/metabolismo , Miocárdio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
8.
Rev Cardiovasc Med ; 20(3): 139-151, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601088

RESUMO

Effective therapy of hypertension represents a key strategy for reducing the burden of cardiovascular disease and its associated mortality. The significance of voltage dependent L-type Ca²âº channels to Ca²âº influx, and of their regulatory mechanisms in the development of heart disease, is well established. A wide variety of L-type Ca²âº channel inhibitors and Ca²âº antagonists have been found to be beneficial not only in the treatment of hypertension, but also in myocardial infarction and heart failure. Over the past two decades, another class of Ca²âº channel - the voltage independent store-operated Ca²âº channel - has been implicated in the regulation and fine tuning of Ca²âº entry in both cardiac and smooth muscle cells. Store-operated Ca²âº channels are activated by the depletion of Ca²âº stores within the endoplasmic/sarcoplasmic reticulum, or by low levels of cytosolic Ca²âº, thereby facilitating agonist-induced Ca²âº influx. Store-operated Ca²âº entry through this pivotal pathway involves both stromal interaction molecule (STIM) and Orai channels. Different degrees of changes in these proteins are considered to promote Ca²âº entry and hence contribute to the pathogenesis of cardiovascular dysfunction. Several blockers of store-operated Ca²âº channels acting at the level of both STIM and Orai channels have been shown to depress Ca²âº influx and lower blood pressure. However, their specificity, safety, and clinical significance remain to be established. Thus, there is an ongoing challenge in the development of selective inhibitors of store-operated Ca²âº channels that act in vascular smooth muscles for the improved treatment of hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Músculo Liso Vascular/efeitos dos fármacos , Moléculas de Interação Estromal/antagonistas & inibidores , Vasodilatadores/uso terapêutico , Animais , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Moléculas de Interação Estromal/metabolismo , Resultado do Tratamento , Vasodilatadores/efeitos adversos
9.
Life Sci ; 237: 116919, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610200

RESUMO

AIMS: Stroke-prone spontaneously hypertensive rats (SHRSP) show significantly lower body weight than normotensive Wistar-Kyoto rats (WKY). Our hypotheses are as follows: weight loss of the skeletal muscle is related to hypertension-related diseases, and muscle hypotrophy is useful as a therapeutic target for hypertension and hypertension-related diseases. In this study, we aimed to investigate the pathophysiological characteristics of muscle hypotrophy in SHRSP to determine the therapeutic target molecule(s). MAIN METHODS: The difference in skeletal muscles in the lower leg between WKY and SHRSP was evaluated mainly through weight/tibial length, histological, gene expression, and protein expression analyses. KEY FINDINGS: SHRSP had a significantly lower weight/tibial length in soleus and gastrocnemius, but not in plantaris and tibialis anterior, indicating that muscles consisting of a relatively high amount of slow muscle fiber were affected. This result was confirmed by the histological analysis of soleus, showing that type I fiber mainly decreased the fiber size. Microarray and protein expression analyses showed that the muscle-specific ubiquitin ligase, muscle RING finger 1 (MuRF1), but not atrogin-1, was highly expressed in soleus, but not in plantaris, in SHRSP. TNF-like weak inducer of apoptosis receptor (TWEAKR) was predicted as a MuRF1 up-regulator by Ingenuity Pathway Analysis and immunostained only in type II fiber in WKY but in both type I and II fibers in SHRSP. SIGNIFICANCE: TWEAKR is a type II-specific receptor in the skeletal muscle. Ectopic TWEAKR expression in type I fiber of SHRSP is most likely involved in slow muscle-specific hypotrophy through MuRF1 overexpression.


Assuntos
Hipertensão/patologia , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Músculo Liso Vascular/patologia , Atrofia Muscular/patologia , Acidente Vascular Cerebral/patologia , Receptor de TWEAK/metabolismo , Animais , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Liso Vascular/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Receptor de TWEAK/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
10.
Hypertension ; 74(5): 1200-1214, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542964

RESUMO

Endothelial cells line all blood vessels and are critical regulators of vascular tone. In hypertension, disruption of endothelial function alters the release of endothelial-derived vasoactive factors and results in increased vascular tone. Although the release of endothelial-derived vasodilators occurs in a Ca2+-dependent manner, little is known on how Ca2+ signaling is altered in hypertension. A key element to endothelial control of vascular tone is Ca2+ signals at specialized regions (myoendothelial projections) that connect endothelial cells and smooth muscle cells. This work describes disruption in the operation of this key Ca2+ signaling pathway in hypertension. We show that vascular reactivity to phenylephrine is increased in hypertensive (spontaneously hypertensive rat) when compared with normotensive (Wistar Kyoto) rats. Basal endothelial Ca2+ activity limits vascular contraction, but that Ca2+-dependent control is impaired in hypertension. When changes in endothelial Ca2+ levels are buffered, vascular contraction to phenylephrine increased, resulting in similar responses in normotension and hypertension. Local endothelial IP3(inositol trisphosphate)-mediated Ca2+ signals are smaller in amplitude, shorter in duration, occur less frequently, and arise from fewer sites in hypertension. Spatial control of endothelial Ca2+ signaling is also disrupted in hypertension: local Ca2+ signals occur further from myoendothelial projections in hypertension. The results demonstrate that the organization of local Ca2+ signaling circuits occurring at myoendothelial projections is disrupted in hypertension, giving rise to increased contractile responses.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Endotélio Vascular/metabolismo , Hipertensão/fisiopatologia , Fenilefrina/farmacologia , Receptores de Detecção de Cálcio/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Valores de Referência , Sensibilidade e Especificidade , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia
11.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514409

RESUMO

Hypertension is the most common modifiable risk factor for stroke, and understanding the underlying mechanisms of hypertension and hypertension-related stroke is crucial. 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE), which plays an important role in vasoconstriction, autoregulation, endothelial dysfunction, angiogenesis, inflammation, and blood-brain barrier integrity, has been linked to hypertension and stroke. 20-HETE can promote hypertension by potentiating the vascular response to vasoconstrictors; it also can reduce blood pressure by inhibition of sodium transport in the kidney. The production of 20-HETE is elevated after the onset of both ischemic and hemorrhagic strokes; on the other hand, subjects with genetic variants in CYP4F2 and CYP4A11 that reduce 20-HETE production are more susceptible to stroke. This review summarizes recent genetic variants in CYP4F2, and CYP4A11 influencing 20-HETE production and discusses the role of 20-HETE in hypertension and the susceptibility to the onset, progression, and prognosis of ischemic and hemorrhagic strokes.


Assuntos
Ácidos Hidroxieicosatetraenoicos/metabolismo , Hipertensão/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Progressão da Doença , Humanos , Modelos Biológicos , Polimorfismo Genético
12.
Nat Med ; 25(9): 1390-1395, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501611

RESUMO

Visceral adipose tissue (VAT)-fat stored around the internal organs-has been suggested as an independent risk factor for cardiovascular and metabolic disease1-3, as well as all-cause, cardiovascular-specific and cancer-specific mortality4,5. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74-0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48-12.0) in females and an odds ratio of 2.50 (95% CI = 1.98-3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.


Assuntos
Adiposidade/genética , Doenças Cardiovasculares/genética , Gordura Intra-Abdominal/metabolismo , Doenças Metabólicas/genética , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Gordura Intra-Abdominal/patologia , Masculino , Análise da Randomização Mendeliana , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Caracteres Sexuais
13.
Hypertension ; 74(4): 854-863, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476910

RESUMO

The Dahl salt-sensitive (SS) rat is an established model of SS hypertension and renal damage. In addition to salt, other dietary components were shown to be important determinants of hypertension in SS rats. With previous work eliminating the involvement of genetic differences, grain-fed SS rats from Charles River Laboratories (SS/CRL; 5L2F/5L79) were less susceptible to salt-induced hypertension and renal damage compared with purified diet-fed SS rats bred at the Medical College of Wisconsin (SS/MCW; 0.4% NaCl, AIN-76A). With the known role of immunity in hypertension, the present study characterized the immune cells infiltrating SS/MCW and SS/CRL kidneys via flow cytometry and RNA sequencing in T-cells isolated from the blood and kidneys of rats maintained on their respective parental diet or on 3 weeks of high salt (4.0% NaCl, AIN-76A). SS/CRL rats were protected from salt-induced hypertension (116.5±1.2 versus 141.9±14.4 mm Hg), albuminuria (21.7±3.5 versus 162.9±22.2 mg/d), and renal immune cell infiltration compared with SS/MCW. RNA-seq revealed >50% of all annotated genes in the entire transcriptome to be significantly differentially expressed in T-cells isolated from blood versus kidney, regardless of colony or chow. Pathway analysis of significantly differentially expressed genes between low and high salt conditions demonstrated changes related to inflammation in SS/MCW renal T-cells compared with metabolism-related pathways in SS/CRL renal T-cells. These functional and transcriptomic T-cell differences between SS/MCW and SS/CRL show that dietary components in addition to salt may influence immunity and the infiltration of immune cells into the kidney, ultimately impacting susceptibility to salt-induced hypertension and renal damage.


Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/patologia , Rim/patologia , Cloreto de Sódio na Dieta/farmacologia , Linfócitos T/metabolismo , Transcriptoma , Animais , Pressão Sanguínea/efeitos dos fármacos , Citometria de Fluxo , Hipertensão/metabolismo , Rim/metabolismo , Masculino , Ratos , Ratos Endogâmicos Dahl
14.
Hypertension ; 74(4): 1021-1032, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401881

RESUMO

Excessive salt consumption leads to cardiovascular diseases. Despite various measures designed to reduce salt intake, daily salt intake remains at a high level. Appropriate salt intake is balanced by salt taste preference triggered by epithelium sodium channel and salt taste aversion evoked by bitter taste sensor, transient receptor potential channel M5 (TRPM5). However, the behavioral mechanism of excessive salt intake remains largely elusive. In this study, wild type and TRPM5-/- mice were applied to study the influence of high-salt administration on epithelium sodium channel/TRPM5 and the associated behavior to salt consumption. We found that long-term high-salt intake impaired the aversive behavior to high-salt stimulation but did not alter the preference to low salt in mice. The mechanistic evidence demonstrated that high-salt intake blunted the TRPM5-mediated aversive behavior to noxious salt stimulation through inhibiting PKC (protein kinase C) activity and PKC-dependent threonine phosphorylation in the tongue epithelium but did not affect the epithelium sodium channel-dependent salt taste preference. Inhibition of TRPM5 also resulted in an impaired aversive response to high salt, with reduced taste perception in bitter cortical field of mice. TRPM5-/- mice showed a lowered aversion to high-salt diet and developed salt-induced hypertension. The impaired perception to bitter taste evoked by high-salt intake also existed in hypertensive patients with high-salt consumption. We demonstrate that long-term high-salt consumption impairs aversive response to concentrated salt by downregulating bitter taste sensor TRPM5. It suggests that enhancing TRPM5 function might antagonize excessive salt intake and high salt-induced hypertension.


Assuntos
Comportamento Alimentar/fisiologia , Hipertensão/metabolismo , Canais de Cátion TRPM/metabolismo , Percepção Gustatória/fisiologia , Paladar/fisiologia , Animais , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Camundongos , Camundongos Knockout , Cloreto de Sódio na Dieta , Canais de Cátion TRPM/genética , Paladar/genética , Percepção Gustatória/genética , Língua/metabolismo
15.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412635

RESUMO

The aim of the present study was to evaluate advanced glycation end products (AGEs) and soluble form of receptor RAGE (sRAGE) concentrations as well as the AGEs/sRAGE ratio in mild (MH) and resistant (RH) hypertensive patients in comparison with normotensive individuals. We also evaluated the association between AGEs, sRAGE as well as AGEs/sRAGE ratio and circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPCs). The MH group consisted of 30 patients, whereas 30 patients were classified for the RH group. The control group (C) included 25 normotensive volunteers. AGEs and sRAGE were measured using enzyme-linked-immunosorbent assay (ELISA). The multicolor flow cytometry was used for analysis of CECs and CEPCs. Significantly higher levels of AGEs in RH cohort were observed as compared to C cohort. Furthermore, significantly lower sRAGE levels as well as a higher AGEs/sRAGE ratio were observed between MH and RH cohorts. Significant correlations were found in the MH cohort for sRAGE and CECs, and CEPCs. The elevation of AGEs levels suggests that oxidative modification of proteins occurs in hypertension pathogenesis. The decrease in sRAGE levels and elevation of the AGEs/sRAGE ratio in MH and RH groups may suggest that hypertensive patients are less protected against the side effects of AGEs as a consequence of an insufficient competitive role of sRAGE against the AGEs-RAGE axis. Finally, it may be concluded that the level of AGEs may be an independent predictor of the condition and function of the endothelium. Furthermore, sRAGE may be classified as a potential biomarker of inflammation and endothelium dysfunction.


Assuntos
Células Endoteliais/metabolismo , Células Progenitoras Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Hipertensão/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Adulto , Idoso , Biomarcadores , Feminino , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oxirredução , Estresse Oxidativo
17.
Georgian Med News ; (291): 58-63, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31418732

RESUMO

Aim - to determine the influence of different levels of lipid metabolism on the relative blood leukocytes telomeres length (RLTL), relative buccal epithelium cells telomeres length (RBTL) in hypertensive (H) individuals with type 2 diabetes mellitus (DM2T) and without DM2T. In 60 patients with H stage II (group 1), and 96 patients with H and DM2T (group 2) lipid metabolism indexes (total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C)), anthropometric parameters were measured. Relative telomeres length (RTL) was determined by a real time quantitative PCR. The most significant shortening of RLTL and RBTL were found in group 2. In both groups, the achievement of target blood lipid levels was accompanied by multidirectional changes in RTL. Analysis of variance revealed a significant effect of TC (p=0.036) on the RBTL, LDL -C (p=0.036) on the RBTL in group 1, and significant influence of TG (p = 0.049) on RBTL, TC (p=0.019) and HDL-C (p=0.032) on RLTL in group 2. Achieving target levels of lipid metabolism did not demonstrate the expected significant effect on the elongation of the relative length of telomeres, both with isolated hypertension and with a combined course of hypertension and DM2T.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Hipertensão/complicações , Hipertensão/metabolismo , Metabolismo dos Lipídeos , Telômero/metabolismo , HDL-Colesterol , LDL-Colesterol , Diabetes Mellitus Tipo 2/genética , Humanos , Hipertensão/genética , Telômero/genética , Encurtamento do Telômero , Triglicerídeos
18.
Hypertension ; 74(4): 910-920, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31422690

RESUMO

Hypertension is associated with increased sympathetic activity. A component of this sympathoexcitation may be driven by increased signaling from sensory endings from the heart to the autonomic control areas in the brain. This pathway mediates the so-called cardiac sympathetic afferent reflex, which is also activated by coronary ischemia or other nociceptive stimuli in the heart. The cardiac sympathetic afferent reflex has been shown to be enhanced in the heart failure state and in renal hypertension. However, little is known about its role in the development or progression of hypertension or the phenotype of the sensory endings involved. To investigate this, we used the selective afferent neurotoxin, resiniferatoxin (RTX) to chronically abolish the cardiac sympathetic afferent reflex in 2 models of hypertension; the spontaneous hypertensive rats (SHRs) and AngII (angiotensin II) infusion (240 ng/kg per min). Blood pressure (BP) was measured in conscious animals for 2 to 8 weeks post-RTX. Epidural application of RTX to the T1-T4 spinal segments prevented the further BP increase in 8-week-old SHR and lowered BP in 16-week-old SHR. RTX did not affect BP in Wistar-Kyoto normotensive rats nor in AngII-infused rats. Epicardial application of RTX (50 µg/mL) in 4-week-old SHR prevented the BP increase whereas this treatment does not lower BP in 16-week-old SHR. When RTX was administered into the L2-L5 spinal segments of 16-week-old SHR, no change in BP was observed. These findings indicate that signaling via thoracic afferent nerve fibers may contribute to the hypertension phenotype in the SHR but not in the Ang II infusion model of hypertension.


Assuntos
Pressão Sanguínea/fisiologia , Gânglios Espinais/metabolismo , Coração/inervação , Hipertensão/metabolismo , Canais de Cátion TRPV/agonistas , Angiotensina II , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Diterpenos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/induzido quimicamente , Masculino , Neurotoxinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos , Reflexo/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo
19.
Int J Mol Sci ; 20(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416126

RESUMO

Mice bearing targeted gene mutations that affect the functions of natriuretic peptides (NPs) and natriuretic peptide receptors (NPRs) have contributed important information on the pathogenesis of hypertension, kidney disease, and cardiovascular dysfunction. Studies of mice having both complete gene disruption and tissue-specific gene ablation have contributed to our understanding of hypertension and cardiovascular disorders. These phenomena are consistent with an oligogenic inheritance in which interactions among a few alleles may account for genetic susceptibility to hypertension, renal insufficiency, and congestive heart failure. In addition to gene knockouts conferring increased risks of hypertension, kidney disorders, and cardiovascular dysfunction, studies of gene duplications have identified mutations that protect against high blood pressure and cardiovascular events, thus generating the notion that certain alleles can confer resistance to hypertension and heart disease. This review focuses on the intriguing phenotypes of Npr1 gene disruption and gene duplication in mice, with emphasis on hypertension and cardiovascular events using mouse models carrying Npr1 gene knockout and/or gene duplication. It also describes how Npr1 gene targeting in mice has contributed to our knowledge of the roles of NPs and NPRs in dose-dependently regulating hypertension and cardiovascular events.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Variação Genética , Guanilato Ciclase/metabolismo , Receptores do Fator Natriurético Atrial/metabolismo , Animais , Biomarcadores , Doenças Cardiovasculares/diagnóstico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Duplicação Gênica , Humanos , Hipertensão/diagnóstico , Hipertensão/etiologia , Hipertensão/metabolismo , Camundongos , Polimorfismo Genético , Disfunção Ventricular Esquerda , Remodelação Ventricular
20.
Int J Mol Sci ; 20(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416234

RESUMO

Hypertension can originate from early-life exposure to oxidative stress. As reported, dimethyl fumarate (DMF) activates nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and protects against oxidative stress damage. We examined whether maternal DMF therapy protects adult offspring against hypertension programmed by prenatal dexamethasone (DEX) and postnatal high-fat (HF) diet exposure. We examined male Sprague Dawley rat offspring at 4 months of age from five groups (n = 11-13/group): control, DEX (0.1mg/kg i.p. from gestational day 16 to 22), HF (D12331 diet from weaning to 16 weeks of age), DEX+HF, and DEX+HF+DMF (50mg/kg/day via gastric gavage for 3 weeks during pregnancy). Maternal DMF therapy prevented male offspring against hypertension programmed by combined DEX and HF exposures. The protective effects of maternal DMF include reduced oxidative stress, decreased plasma asymmetric dimethylarginine (ADMA) levels, downregulated the renin-angiotensin system (i.e. Ren, Agt, Ace, and Agtr1a), increased renal protein levels of certain nutrient-sensing signals, and promoted autophagy. In conclusion, maternal Nrf2 activation by DMF protects male adult offspring against hypertension programmed by combined DEX and HF exposures. Our results cast a new light on the therapeutic potential of targeting Nrf2 signaling pathway as reprogramming strategies to prevent programmed hypertension in children exposed to antenatal corticosteroids and postnatally excessive consumption of fat.


Assuntos
Dexametasona/administração & dosagem , Dieta Hiperlipídica , Fumarato de Dimetilo/administração & dosagem , Hipertensão/etiologia , Hipertensão/prevenção & controle , Exposição Materna , Fator 2 Relacionado a NF-E2/agonistas , Efeitos Tardios da Exposição Pré-Natal , Animais , Biomarcadores , Feminino , Expressão Gênica , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Recém-Nascido , Masculino , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Fosforilação , Gravidez , Ratos
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